CaMKII is a leading candidate as a molecular memory. In a first aim, we will explore the hypothesis that CaMKII and phosphatase-1 (PP1) in the postsynaptic density (PSD) form a bistable switch. Monte Carlo simulations will be developed. The model will be used to address a fundamental theoretical question: how is the stability of stored information limited by stochastic fluctuations in the reactions of the small group of molecules at synapses? In a parallel set of biochemical experiments, we will directly test whether the CaMKII/PP1 system in isolated PSDs can act as a bistable switch. In Aim 2 we examine how synaptic strength can be bi-directionally modified by different patterns of synaptic activation. The moderate Ca2+ elevation during the induction of depotentiation reduces CaMKII phosphorylation through a phosphatase cascade that involves calcineurin, I1 and PP1. Since <1% of synapses are activated during induction active synapses are point sinks/sources, producing dendritic gradients of diffusible molecules such as I1. The buildup of such gradients could potentially explain kinetic aspects of induction and heterosynaptic effects. Because the role of gradients has not been previously considered, it will be useful to make a diffusion model to study how different factors affect the spatial/temporal gradient of possible importance in plasticity. In related physiological experiments, we will test the role of I1 in depotentiation. Aim 3 relates to recent work indicating that LTP produces a stable increase in synapse size. To understand the principles that might underlie such structural stability, we have formed a team with expertise in physical chemistry, structural biology, neuroscience and physics. Simulations will be used to explore the principles that could underlie structural stability. Together these aims address the deepest issues regard the mechanism by which memories are stored in the brain. The insights derived are likely to be of importance in understanding diseases of memory and suggest strategies for therapeutic intervention.